ClinVar Genomic variation as it relates to human health
NM_000329.3(RPE65):c.952T>A (p.Tyr318Asn)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000329.3(RPE65):c.952T>A (p.Tyr318Asn)
Variation ID: 98900 Accession: VCV000098900.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p31.3 1: 68438988 (GRCh38) [ NCBI UCSC ] 1: 68904671 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 20, 2014 Feb 28, 2024 Oct 26, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000329.3:c.952T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000320.1:p.Tyr318Asn missense NC_000001.11:g.68438988A>T NC_000001.10:g.68904671A>T NG_008472.2:g.15972T>A - Protein change
- Y318N
- Other names
- -
- Canonical SPDI
- NC_000001.11:68438987:A:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00006
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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RPE65 | - | - |
GRCh38 GRCh37 |
944 | 970 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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not provided (1) |
no classification provided
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- | RCV000085233.3 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 12, 2023 | RCV001089895.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 26, 2023 | RCV001854499.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 19, 2023 | RCV003323394.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jul 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Leber congenital amaurosis
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004028604.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
Comment:
Variant summary: RPE65 c.952T>A (p.Tyr318Asn) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: RPE65 c.952T>A (p.Tyr318Asn) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251368 control chromosomes. c.952T>A has been reported in the literature in the compound heterozygous state together with a pathogenic variant in at least three individuals affected with Leber Congenital Amaurosis or an inherited retinal disease (e.g. Weleber_2016, Kumaran_2018, Sheck_2021) and has been reported as an unspecified genotype in an individual in a Leber Congenital Amaurosis cohort (Stone_2007). These data indicate that the variant is likely associated with disease. At least two publications report experimental evidence evaluating an impact on protein function and both found the variant had decreased protein expression levels and resulted in <10% of normal activity (e.g. Philip_2009, Li_2014). The following publications have been ascertained in the context of this evaluation (PMID: 30268864, 29332120, 24849605, 19431183, 33749171, 17964524, 27102010, 16123401). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Sep 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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Leber congenital amaurosis 2
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004209234.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Oct 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Leber congenital amaurosis 2
Retinitis pigmentosa 20
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002265097.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 318 of the RPE65 protein (p.Tyr318Asn). … (more)
This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 318 of the RPE65 protein (p.Tyr318Asn). This variant is present in population databases (rs61752905, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive Leber congenital amaurosis and/or retinitis pigmentosa (PMID: 29332120; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 98900). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RPE65 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RPE65 function (PMID: 19431183, 24849605). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Feb 14, 2020)
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criteria provided, single submitter
Method: curation
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Leber congenital amaurosis 2
Affected status: unknown
Allele origin:
unknown
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SIB Swiss Institute of Bioinformatics
Accession: SCV001245402.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
Comment:
This variant is interpreted as likely pathogenic for Leber congenital amaurosis 2, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PP3, PS3.
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Likely pathogenic
(-)
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no assertion criteria provided
Method: research
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Leber congenital amaurosis 2
Affected status: yes
Allele origin:
inherited
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Laboratory of Genetics in Ophthalmology, Institut Imagine
Accession: SCV001425562.1
First in ClinVar: Jul 30, 2020 Last updated: Jul 30, 2020 |
Number of individuals with the variant: 3
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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Retina International
Accession: SCV000117370.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014
Comment:
http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg19&id=RISN_RPE65:c.952T>A
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Panel-based genetic testing for inherited retinal disease screening 176 genes. | Sheck LHN | Molecular genetics & genomic medicine | 2021 | PMID: 33749171 |
The Natural History of Inherited Retinal Dystrophy Due to Biallelic Mutations in the RPE65 Gene. | Chung DC | American journal of ophthalmology | 2019 | PMID: 30268864 |
Severe Loss of Tritan Color Discrimination in RPE65 Associated Leber Congenital Amaurosis. | Kumaran N | Investigative ophthalmology & visual science | 2018 | PMID: 29332120 |
Results at 2 Years after Gene Therapy for RPE65-Deficient Leber Congenital Amaurosis and Severe Early-Childhood-Onset Retinal Dystrophy. | Weleber RG | Ophthalmology | 2016 | PMID: 27102010 |
Rescue of enzymatic function for disease-associated RPE65 proteins containing various missense mutations in non-active sites. | Li S | The Journal of biological chemistry | 2014 | PMID: 24849605 |
Predicting the pathogenicity of RPE65 mutations. | Philp AR | Human mutation | 2009 | PMID: 19431183 |
Leber congenital amaurosis - a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture. | Stone EM | American journal of ophthalmology | 2007 | PMID: 17964524 |
Genotyping microarray (disease chip) for Leber congenital amaurosis: detection of modifier alleles. | Zernant J | Investigative ophthalmology & visual science | 2005 | PMID: 16123401 |
Text-mined citations for rs61752905 ...
HelpRecord last updated Mar 05, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.